This application addresses broad Challenge Area (03) Biomarker Research and the specific Challenge Area 03-HL-101: "Identify and validate clinically relevant, quantifiable biomarkers" Background: The population attributable fraction (PAF) estimates the amount of a disease that is due to a specific factor, quantifying the burden of disease that would be prevented if that factor was eliminated. For selected orphan lung diseases, quantifying the environmentally-related PAF would provide important guidance for clinicians in diagnosis and disease management and for prevention strategies to reduce the burden of new disease prospectively. Linking biomarker data to other metrics of exposure in an integrated risk modeling approach will yield more accurate PAF estimates. Hypersensitivity pneumonitis (HP) and pulmonary alveolar proteinosis (PAP) are ideal candidate diseases for which to apply this biomarker-linked PAF strategy. Aims: For HP, identifying the relative contributions of currently known environmental factors, as well as un- identified causes, in particular "non-specified" indoor air sources. For PAP, estimating the PAF linked to dust inhalation, in particular silica (including concrete construction) in salaried occupations as well as in non- salaried avocations and, potentially, through ambient point sources. For both HP and PAP, evaluating the association between selected risk factors and disease activity-severity using selected biomarker data to differentiate among cases and between cases and referents. Experimental Plan: Cases and referents recruited through the data base of the Kaiser Permanente Health Plan (KPHP). The case pool will be supplemented through additional recruitment from a University-based sub- specialty pulmonary practice (UCSF). Target recruitment will yield interviews in 125 HP cases and matching referents with home visits in 75 of each;for PAP, 46 interviews and 25 home visits plus referents. Environ- mental exposures and biomarkers will assessed through structured interviews and through home visits. Residential addresses will be geocoded for linkage to supplemental environmental exposure data. Medical record extraction (cases only) will be used to confirm diagnostic consistency and supplement measures of disease severity. Cases will be compared to referents for environmental exposures and biomarkers of disease. Differences between cases and referents for continuous measures will be tested using approaches for continuous parametric and non-parametric variables and Odds Ratios for dichotomous measures, the PAF for the environmentally-related burden of disease will be estimated. Significance: The varying contributions of occupation, outdoor ambient pollution, and home indoor exposures to HP and PAP are likely to be relevant not only for patient diagnosis but also for management and clinical outcomes. Linking biomarker data to other metrics of exposure in an integrated risk modeling approach is key to deriving more accurate PAF estimates, which is why this Challenge Area is so relevant to this question. 7. Project Narrative The goal of this study is to estimate the relative contributions selected environmental risk factors to the burden to two orphan lung diseases, hypersensitivity pneumonitis and pulmonary alveolar proteinosis. Using environmental exposure data, supplemented with biomarker data relevant to disease activity and severity, this project will lead to findings relevant to disease prevention for these specific conditions and, by application of the approach, potentially to other orphan disease as well.